The invention relates to a predictive scoring function for estimating binding affinity.
A great majority of pharmaceutically active compounds derive efficacy from binding to targeted receptors which are often proteins (a term that includes glycoproteins and lipoproteins). Approximately 50 years ago, the first high resolution structure of a protein was determined via x-ray crystallography. The publicly accessible protein data bank (PDB) now contains more than 10,000 such structures, and pharmaceutical and biotechnology companies have an order of magnitude more proprietary structures. Many of these structures have been co-crystallized with small molecules bound to them. The examination of such structures, and deployment of the knowledge thereby gained to design new, more potent, and more specific inhibitors, is referred to as structure-based drug design.
Computational modeling facilitates structure-based drug design. Given a high resolution protein structure, computational software is used to “dock” a small molecule ligand into the correct position and orient it in the protein active site cavity, and calculate a binding affinity of the ligand given this structure. Computer software programs that perform this task are referred to as “docking” programs.
A docking program typically carries out two distinct tasks to model protein-ligand binding. First, a structure of a protein-ligand complex is predicted. In high throughput docking, a receptor (e.g., protein) is ordinarily assumed to be rigid. When this assumption fails, use of a different structure of the receptor as a starting point is required. The problem of constructing alternative receptor structures that are modified to accept ligands requiring a substantial change in receptor conformation (“induced fit”) is a very important one. We focus here on cases where docking of the ligand into a rigid receptor yields a structure in reasonable agreement with experimental data. This will be the case when, in the docked structure, the ligand in the docked structure makes key hydrogen bonds and hydrophobic contacts with the protein in good agreement with the experimental data.
A second task of the docking program is to calculate a protein-ligand binding affinity, given as an input the docked structure. A mathematical function employed to calculate the binding affinity is referred to as a “scoring function.” Despite intensive effort over several decades, in many situations, presently available scoring functions are unsatisfactory with regard to the desired accuracy and robustness.